Diabetes is a major health concern in the United States and worldwide. Both type I and type II diabetes not only severely compromise the health of the afflicted individual, but diabetes also affects embryonic development. Maternal diabetes during pregnancy has well-documented teratogenic effects that cause birth defects such as cardiovascular malformations and neural tube defects. Those effects are not well understood, but are thought to involve interactions of the embryo's genetic makeup with the intrauterine environment. The goal of this project is to understand how maternal diabetes affects the developing embryo, with focus on the early nervous system and the pathogenesis of neural tube defects. Our key hypothesis is that abnormal maternal metabolism in diabetic pregnancy de-regulates gene expression during early nervous system development in the embryo, thereby leading to an increased incidence of neural tube defects. The basis for this hypothesis is our recent discovery of 143 genes whose expression is significantly changed in mouse embryos exposed to maternal diabetes during development. Many of these genes are already known to be involved in birth defects, and a subset of these genes play a role in neural tube defects. We now propose (1) to define which genes are most indicative and can serve as predictive markers for failure of the neural tube to close properly; (2) to investigate how an altered hypoxia response, in particular reduced Hifla expression as found in diabetes-exposed embryos, compromises the embryo's ability to successfully adapt to the adverse intrauterine environment; (3) to determine how the diabetes regulated genes PdgfRa and Vinculin mediate the susceptibility to neural tube defects as consequence of the intrauterine exposure to maternal diabetes. With increasing prevalence of diabetes in younger women in the United States, prenatal exposure of the next generation becomes a major health concern. Exposure to diabetes in utero is a known risk for severe birth defects and for chronic disease, such as metabolic syndrome, hypertension and cardiovascular disease. Understanding the specific genetic factors in the developing embryo that respond to maternal diabetes will form the basis for future strategies to prevent the adverse outcomes of diabetic pregnancies. [unreadable] [unreadable] [unreadable]